Pancreatic cancer is one of the most lethal malignancies in humans and there is no effective conventional treatment available for the cure of patients with pancreatic cancer. Crocetin, a carotenoid molecule isolated from saffron, has been demonstrated recently by our laboratory to have potent antimitotic effects both in in vitro and in vivo pancreatic cancer models. Commercial crocetin is a mixture of crocetinic acid and crocetin esters. We have recently fractionated commercial crocetin using preparative HPLC, and demonstrated that crocetinic acid is the most active component. The goal of this proposal is to identify all of the active components in crocetin, and determine the signaling mechanisms, responsible for inducing cellular proliferation and tumorigenesis of pancreatic adenocarcinoma that are impaired by purified crocetin components. Our central hypothesis is that crocetin inhibits cellular proliferation and stimulates apoptosis signaling pathways due to the impairment of histone modifications in pancreatic adenocarcinoma. The long term goal is to develop crocetin as therapeutic and chemopreventive agent. To test this hypothesis, four specific aims are proposed. Aim 1 (a): To purify, identify, and characterize the active components present in commercial preparations of crocetin. Aim 1 (b): To determine the pharmacokinetics of crocetin in pancreatic cancer in in vitro and in vivo models. Aim 2 : To determine purified crocetin-mediated regulation of i) histone modifications by acetylation, ii) inhibition of proliferation and iii) stimulation of apoptosis using in vitro pancreatic cancer models. The status of migration and invasion will be investigated in in vitro models. Aim 3: To determine purified crocetin mediated regression of pancreatic cancer in a xenograft mouse model. Aim 4: To determine whether purified crocetin will enhance the efficacy of conventional chemothrapeutic agents (gemcitabine [Gemzar] and/or 5-FU [Fluorouracil]) in impairing cell proliferation and the induction of apoptosis of pancreatic cancer cells in in vitro and in vivo models.. This is the first study to evaluate the effectiveness of novel crocetin in pancreatic cancer. This proposal will provide further evidence to justify and enocourage Phase I clinical trials using crocetin. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is one of the most lethal malignancies and there is no effective conventional treatment in pancreatic cancer. This exploratory RO-1 proposal will offer a promise for developing a novel crocetin compound derived from saffron for therapy with known anticancer agents in pancreatic cancer.